Antigen Burden Is a Major Determinant of Human Immunodeficiency Virus–Specific CD8<sup>+</sup>T Cell Maturation State: Potential Implications for Therapeutic Immunization

Tussey, Lynda; Nair, U.; Bachinsky, Margaret; Edwards, Bradley H.; Bakari, Janna; Grimm, Karen M.; Joyce, Joseph G.; Vessey, Rupert; Steigbigel, Roy T.; Robertson, Michael; Shiver, John W.; Goepfert, Paul

doi:10.1086/367707

Cited by 57 publications

(39 citation statements)

References 43 publications

(61 reference statements)

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“…Currently, there is no clear consensus on the pathways of memory/effector T cell differentiation, and several models have been proposed (2,3,6,7,(22)(23)(24)(25)(26)(27). Studies in mice suggest that nonlymphoid tissues are preferentially populated by a subset of CD8 ϩ T cells (9,28).…”

Section: Discussionmentioning

confidence: 99%

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Breast Milk-Derived Antigen-Specific CD8+ T Cells: An Extralymphoid Effector Memory Cell Population in Humans

Sabbaj

Ghosh

Edwards

et al. 2005

The Journal of Immunology

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Although mouse studies have demonstrated the presence of an effector memory population in nonlymphoid tissues, the phenotype of human CD8+ T cells present in such compartments has not been characterized. Because of the relatively large number of CD8+ T cells present in breast milk, we were able to characterize the phenotype of this cell population in HIV-infected and uninfected lactating women. CMV, influenza virus, EBV, and HIV-specific CD8+ T cells as measured by the IFN-γ ELISPOT and MHC class I tetramer staining were all present at greater frequencies in breast milk as compared with blood. Furthermore, a greater percentage of the breast milk CD8+ T cells expressed the intestinal homing receptor, CD103, and the mucosal homing receptor CCR9. Breast milk T cells were predominantly CD45RO+HLADR+ and expressed low levels of CD45RA, CD62L, and CCR7 consistent with an effector memory population. Conversely, T cells derived from blood were mainly characterized as central memory cells (CCR7+CD62L+). These results demonstrate a population of extralymphoid CD8+ T cells with an effector memory phenotype in humans, which could contribute to enhanced local virologic control and the relative lack of HIV transmission via this route.

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Section: Discussionmentioning

confidence: 99%

“…respectively, and have been used by others to distinguish between subsets of differentiated CD8 ϩ T cells (4,6). CD28 seems to be expressed at higher levels on the surface of BMC, whereas CD27 appears to be present at similar levels on both BMC and PBMC (Fig.…”

Section: T Cells From Bmc and Pbmcmentioning

confidence: 99%

Breast Milk-Derived Antigen-Specific CD8+ T Cells: An Extralymphoid Effector Memory Cell Population in Humans

Sabbaj

Ghosh

Edwards

et al. 2005

The Journal of Immunology

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“…CD45RA is expressed on naive cells, but can be re-expressed on memory cells in both humans and macaques (39). In combination with CD28, CD45RA expression can be used to further distinguish memory subsets (35). After prime-boost vaccination and challenge in animals 5821 and 5827, there was minimal loss of CD27 expression, although CD28 expression reduced over time after vaccination and was regained in a significant proportion of KP9-specific cells after challenge (Fig.…”

Section: Memory Phenotyping Of Kp9-specific Cd8mentioning

confidence: 99%

“…Staining for memory markers was conducted as described elsewhere (35,36). Whole blood was stained with the Mane-A*10/KP9 tetramer and anti-CD3 PerCP (BD, clone SP34-2; BD Biosciences), anti-CD8 PE-Cy7 (clone SK1; BD Biosciences) in combination with anti-CD28 allophycocyanin (clone 28.2; BD Biosciences), and anti-CD27 FITC (clone M-T271; BD Biosciences) or anti-CD45RA FITC (clone 5H9; BD Biosciences).…”

Section: Lymphocyte Phenotyping For Memory Markersmentioning

confidence: 99%

Killing Kinetics of Simian Immunodeficiency Virus-Specific CD8+ T Cells: Implications for HIV Vaccine Strategies

Rollman

Smith

Brööks

et al. 2007

The Journal of Immunology

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Both the magnitude and function of vaccine-induced HIV-specific CD8+ CTLs are likely to be important in the outcome of infection. We hypothesized that rapid cytolysis by CTLs may facilitate control of viral challenge. Release kinetics of the cytolytic effector molecules granzyme B and perforin, as well as the expression of the degranulation marker CD107a and IFN-γ were simultaneously studied in SIV Gag164–172 KP9-specific CD8+ T cells from Mane-A*10+ pigtail macaques. Macaques were vaccinated with either prime-boost poxvirus vector vaccines or live-attenuated SIV vaccines. Prime-boost vaccination induced Gag-specific CTLs capable of only slow (after 3 h) production of IFN-γ and with limited (<5%) degranulation and granzyme B release. Vaccination with live-attenuated SIV resulted in a rapid cytolytic profile of SIV-specific CTLs with rapid (<0.5 h) and robust (>50% of tetramer-positive CD8+ T cells) degranulation and granzyme B release. The cytolytic phenotype following live-attenuated SIV vaccinations were similar to that associated with the partial resolution of viremia following SIVmac251 challenge of prime-boost-vaccinated macaques, albeit with less IFN-γ expression. High proportions of KP9-specific T cells expressed the costimulatory molecule CD28 when they exhibited a rapid cytolytic phenotype. The delayed cytolytic phenotype exhibited by standard vector-based vaccine-induced CTLs may limit the ability of T cell-based HIV vaccines to rapidly control acute infection following a pathogenic lentiviral exposure.

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“…It is still debated, however, whether high levels of antigen presentation are the cause of T-cell exhaustion or whether T-cell exhaustion is the cause for the high antigen levels. Several reports support the notion that the level of antigen exposure is indeed directly affecting the function of CD8 1 T cells: (i) reduction of antigen load (either naturally in later stages of LCMV infection, or via Nef-mediated downregulation of HLA-A and B molecules or druginduced in human HIV infection or due to the selection of T-cell epitope escape variants) leads to a slow reversal of CD8 1 T-cell dysfunction [4,35,37,79,80]; (ii) impairment of cytokine production by virus-specific CD8 1 T cells is delayed in chronically LCMV-infected mice, which can only present viral antigens on hematopoietic cells [34]; iii) repeated infection of mice with influenza A virus and therefore repeated stimulation with antigen leads to a slight impairment of T-cell function [36]; and (iv) viral infections with much lower antigen loads such as reactivating herpes virus infections are generally associated with functional T-cell responses and mildly dysfunctional cells might only be apparent during very late stages of infection [66,81,82].…”

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confidence: 99%

How chronic viral infections impact on antigen‐specific T‐cell responses

2010

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Persistent viral infections are, by definition, associated with ineffective antiviral immunity, in particular those infections caused by viruses that are highly productive and replicative (including HIV, HBV and HCV). The reasons for ineffective antiviral immunity in these types of infections are complex and manifold, and only recently a more comprehensive picture of the parameters responsible for attenuation of immune function is emerging. One reason for poor viral control in these types of infections is the functional deterioration of antiviral T-cell responses and understanding the underlying mechanisms is of key importance. This review summarizes our current knowledge of cell-intrinsic and cellextrinsic parameters that contribute to T-cell exhaustion during chronic viral infections and discusses related implications for host survival, immunopathology, and control of infection. Key words: Persistent viral infection . T-cell dysfunction . T-cell immunity IntroductionPersistent viral infections, by definition, are not entirely controlled by the host's immune system and are often associated with relevant clinical disease outcomes. Persistent viral infections can be roughly divided into (i) highly productive and replicative infections (associated with continued high abundance of viral antigens) and (ii) latent/reactivating infections (associated with low and perhaps sporadic levels of viral antigens). Well-known examples of the former are HIV, HBV and HCV, which together infect more than 2 billion people worldwide (http://www. unaids.org/; http://www.epidemic.org/; http://www.hepb.org/), and lymphocytic choriomeningitis virus (LCMV) infection in the mouse. Examples of the latter are herpes virus infections, including EBV, CMV, and HSV, which affect together almost 100% of the population. Viruses falling into these two categories have evolved very diverse strategies for co-existence in an immunocompetent host. Highly productive and replicative viruses tend to induce impaired virus-specific adaptive immune responses, which are characterized by limited and dysfunctional T-cell responses, and mutational escape from immune (or drug) pressure are common features of these viruses. Viruses causing latent/reactivating infections have, as a result of their large coding capacity, evolved strategies to interfere with host immunity (immune evasion mechanisms) and have acquired genetic programs that permit a latent, non-replicative existence of the viral genetic information with the option of resuming viral replication in response to certain stimuli. These viral reactivation events, however, are generally well controlled by host immunity and only become clinically apparent in circumstances of immunosuppression.This review focuses on highly productive and replicative persistent viral infections (hereafter referred to as persistent viral infection) with specific emphasis on cell-intrinsic and -extrinsic mechanisms responsible for constraining the size of the antiviral T-cell response and for T-cell dysfunction (summarized in Fig...

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Antigen Burden Is a Major Determinant of Human Immunodeficiency Virus–Specific CD8⁺T Cell Maturation State: Potential Implications for Therapeutic Immunization

Cited by 57 publications

References 43 publications

Breast Milk-Derived Antigen-Specific CD8+ T Cells: An Extralymphoid Effector Memory Cell Population in Humans

Breast Milk-Derived Antigen-Specific CD8+ T Cells: An Extralymphoid Effector Memory Cell Population in Humans

Killing Kinetics of Simian Immunodeficiency Virus-Specific CD8+ T Cells: Implications for HIV Vaccine Strategies

How chronic viral infections impact on antigen‐specific T‐cell responses

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Antigen Burden Is a Major Determinant of Human Immunodeficiency Virus–Specific CD8+T Cell Maturation State: Potential Implications for Therapeutic Immunization

Cited by 57 publications

References 43 publications

Breast Milk-Derived Antigen-Specific CD8+ T Cells: An Extralymphoid Effector Memory Cell Population in Humans

Breast Milk-Derived Antigen-Specific CD8+ T Cells: An Extralymphoid Effector Memory Cell Population in Humans

Killing Kinetics of Simian Immunodeficiency Virus-Specific CD8+ T Cells: Implications for HIV Vaccine Strategies

How chronic viral infections impact on antigen‐specific T‐cell responses

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Product

Resources

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Antigen Burden Is a Major Determinant of Human Immunodeficiency Virus–Specific CD8⁺T Cell Maturation State: Potential Implications for Therapeutic Immunization